Enhancement of antibody-dependent mechanisms of tumor cell lysis by a targeted activator of complement

• Published in: Cancer research (Chicago, Ill.) Vol. 67; no. 19; pp. 9535 - 9541
• Main Authors: IMAI, Masaki, OHTA, Rieko, VARELA, Juan C, SONG, Hongbin, TOMLINSON, Stephen
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01-10-2007
• Subjects: Animals; Antibodies, Monoclonal - immunology; Antibody-Dependent Cell Cytotoxicity; Antigens, Neoplasm - immunology; Antineoplastic agents; Biological and medical sciences; Complement Activation - immunology; Humans; Immunoglobulin G - immunology; Immunotherapy - methods; Male; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Nude; Mucin-1 - immunology; Pharmacology. Drug treatments; Prostatic Neoplasms - immunology; Prostatic Neoplasms - therapy; Receptors, Complement 3d - genetics; Receptors, Complement 3d - immunology; Receptors, Fc - genetics; Receptors, Fc - immunology; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - immunology; Recombinant Fusion Proteins - isolation & purification; Recombinant Fusion Proteins - pharmacology; Tumors; Cytolysis; Target; Targeting; Activator; Antibody; Complement; Malignant tumor; Mechanism of action; Tumor cell
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-07-1690

Complement inhibitors expressed on tumor cells provide a hindrance to the therapeutic efficacy of some monoclonal antibodies (mAb). We investigated a novel strategy to overwhelm complement inhibitor activity and amplify complement activation on tumor cells. The C3-binding domain of human complement receptor 2 (CR2; CD21) was linked to the complement-activating Fc region of human IgG1 (CR2-Fc), and the ability of the construct to target and amplify complement deposition on tumor cells was investigated. CR2 binds C3 activation fragments, and CR2-Fc targeted tumor cells by binding to C3 initially deposited by a tumor-specific antibody. Complement deposition on Du145 cells (human prostate cancer cell line) and anti-MUC1 mAb-mediated complement-dependent lysis of Du145 cells were significantly enhanced by CR2-Fc. Anti-MUC1 antibody-dependent cell-mediated cytotoxicity of Du145 by human peripheral blood mononuclear cells was also significantly enhanced by CR2-Fc in both the presence and the absence of complement. Radiolabeled CR2-Fc targeted to s.c. Du145 tumors in nude mice treated with anti-MUC1 mAb, validating the targeting strategy in vivo. A metastatic model was used to investigate the effect of CR2-Fc in a therapeutic paradigm. Administration of CR2-Fc together with mAb therapy significantly improved long-term survival of nude mice challenged with an i.v. injection of EL4 cells. The data show that CR2-Fc enhances the therapeutic efficacy of antibody therapy, and the construct may provide particular benefits under conditions of limiting antibody concentration or low tumor antigen density.